Three basic types of glial cell are found in the human retina, Muller cells,
astroglia and microglia. All were described for the retina by Cajal more than one hundred years ago (1892).

1. Muller cells.

Muller cells are the principal glial cell of the retina. They form
architectural support structures stretching radially across the thickness of
the retina and are the limits of the retina at the outer and inner limiting
membrane respectively. A complete understanding of the shape of a Muller cell
is best seen after Golgi staining as shown originally by Cajal (1892) (Fig 1a) or by anti-vimentin antibody staining (Fig 1b).

Muller cell bodies sit in the inner nuclear layer and project irregularly
thick and thin processes in either direction vertically to the outer limiting membrane (OLM, Fig 1b) and
to the inner limiting membrane (ILM, Fig 1b). Muller cell processes insinuate themselves between cell bodies of the neurons in the nuclear layers and envelope groups of neural processes in the plexiform layers (Fig. 1a and b). In fact retinal neural processes are only allowed direct contact, without enveloping Muller cell processes, at their synapses.

A single progenitor cell gives rise to both Muller cells and retinal neurons(Turner and Cepko, 1987) although apparently in two phases. The earliest phase neurons born at the apical margin of the neuroepithelium adjacent to the
pigment epithelium produces primary neurons consisting of cone cells,
horizontal cells and ganglion cells (Fig. 2, right). The second phase of cells also born at the
apical margins produces Muller cells and rod photoreceptors, bipolar cells and
amacrine cells (Reichenbach and Robinson, 1995) (Fig. 2, left). All the developing neurons
and the Muller cells have to migrate inward to their final position and it is
thought that the Muller cell processes and trunks guide much of the neuron
migrations and direct the neurite differentiations.

The junctions forming the outer limiting membrane are between Muller
cells and other Muller cells and photoreceptor cells as sturdy desmosomes or
zonula adherens. In some species gap junctions (specialized membrane
associations and channels that allow passage of small molecules and ions) or
tight junctions are part of these Muller cell junctions (Miller and Dowling,
1970) but not so in mammalian species where no dye coupling has ever been
observed (Robinson et al., 1993; Reichenbach and Robinson, 1995). The surface
of the Muller cell facing the pigment epithelium and subretinal space is
expanded by many projections of the Muller cell membrane known as apical villi.
The inner limiting membrane, on the other hand, is formed by the conical
endfeet of the Muller cell but no specialized junctions are seen here. Muller
cells also form endfeet on the large retinal blood vessels at the inner surface
of the retina. The surface of the Muller cell membrane facing the vitreous is
covered with a mucopolysaccharide material and thus forms a true basement
membrane.

Muller cells contain glycogen, mitochondria and intermediate filaments which are immunoreative for vimentin and to some extent to glial fibrillary acidicprotein (GFAP). The latter filaments are normally in the inner half of the retinal Muller cells and their endfeet (Fig. 3, left), but following trauma to the retina such as retinal detachment, both vimentin and GFAP are massively upregulated and found throughout the cell (Fig. 3, right) (Guerin et al., 1990; Fisher and Lewis,
1995).

Muller cells have a range of functions all of which are vital to the health of
the retinal neurons. Muller cells function in a symbiotic relationship with the
neurons (for an excellent review see Reichenbach and Robinson, 1995). Thus
Muller cell functions include:

Supplying endproducts of anaerobic metabolism (breakdown of glycogen) to
fuel aerobic metabolism in the nerve cells.

They mop up neural waste products such as carbon dioxide and ammonia and
recycle spent amino acid transmitters.

They protect neurons from exposure to excess neurotransmitters such as
glutamate using well developed uptake mechanisms to recycle this transmitter.
They are particularly characterized by the presence of high concentrations of
glutamine synthase.

They may be involved in both phagocytosis of neuronal debris and release of
neuroactive substances such as GABA, taurine and dopamine.

They are thought to synthesize retinoic acid from retinol (retinoic acid is
known to be important in in the development of the eye and the nervous system)
(Edwards, 1994)

They control homeostasis and protect neurons from deleterious changes in
their ionic environment by taking up extracellular K+ and redistributing it.

They contribute to the generation of the electroretinogram (ERG) b-wave
(Miller and Dowling, 1970; Newman and Odette, 1984), the slow P3 component of
the ERG (Karwoski and Proenza, 1977) and the scotopic threshold response (STR)
(Frishman and Steinberg, 1989). They do so by regulation of K+ distribution
across the retinal vitreous border, across the whole retina and locally in the
inner plexiform layer of the retina (Fig. 4, from Reichenbach and
Robinson, 1995, adapted from Newman, 1989).

Astrocytes are not glial cells of the retinal neuroepithelium but
enter the developing retina from the brain along the developing optic nerve
(Stone and Dreher, 1987; Chan-Ling 1994). They have a characterisic morphology
of a flattened cell body and a fibrous series of radiating processes.
Intermediate filaments fill their processes and thus they stain dramatically
with antibodies against GFAP (Schnitzer, 1988). Astrocyte cell bodies and
processes are almost entirely restricted to the nerve fiber layer of the
retina. Their morphology changes from the periphery to the optic nerve head:
from a symmetrical stellate form in peripheral retina (Figs. 5a and b) (Schitzer, 1988) to extremely elongated near the optic nerve (Fig. 6 and 7).

In immunocytochemical staining (Fig. 5b) and in HRP intracellular injections (Fig. 7) stained astrocytes clearly exhibit processes aligned along the ganglion cell axons coursing through the nerve fibre layer. In distribution, astrocytes reach their peak on the optic nerve head and have a fairly uniform decline in density in radiating rings from the nerve head. They are not present in the avascular fovea or ora serrata.

Thick and thin astrocytes have been distinguished on the basis of staining
with antibodies to GFAP (Trevino et al., 1996). Thus astrocytes are arranged
over the surface of the ganglion cell axon bundles as they course into the
optic nerve head forming a tube through which the axons run (Fig. 8). Gap junctions and
zonula adherens junctions have been described between astrocytic processes in
cat retina (Höllander et al., 1991).

The blood vessels running in and among the ganglion cell bundles are also
covered by by both processes and even an occasional cell body of an astrocyte.
The function of astrocytes enveloping ganglion cell axons and the relationship
to blood vessels of the nerve fibre layer suggests they are axonal and vascular
glial sheaths and part of a blood-brain barrier. Similar to Muller cells, they
are known to contain abundant glycogen and they may form a nutritive service in
providing glucose to the neurons. In addition they probably serve a role in
ionic homeostasis in regulating extracellular potassium levels and metabolism
of neurotransmitters like GABA.

The third glial cell type is supposedly of mesodermal origin and thus,
strictly speaking are not neuroglial as are the astrocytes and Muller cells. They enter the retina coincident with the mesenchymal precursors of
retinal blood vessels in development (Chan-Ling, 1994). Microglial cells are
ubiquitous in the human retina being found in every layer of the retina.

In Golgi-stained retina they look like strange, multipolar forms with small cell bodies and irregular short processes. In fact, in Golgi preparations they have
sometimes been mistaken for nerve cells particularly when they lie in a nuclear
layer with a single orientation of their processes in the plexiform layer.

Microglial cells may be of two types. One form is thought to enter the retina at
early stages of development from the optic nerve mesenchyme and lie dormant
in the retinal layers for much of the life of the retina. The other form of
microglia appear to be blood-borne cells, possible originating from vessel
pericytes (Boycott and Hopkins, 1981; Gallego, 1986). Both types can be
stimulated into a macrophagic function after trauma to the retina, and then they
engage in phagocytosis of degenerating retinal neurons.